Arthritis is the most frequently reported chronic condition among American females and the second most frequent overall. Certain cytokines such as TNF-alpha and interleukin-1 have been shown to be key mediators in the arthritic disease state. To overcome problems associated with delivery of anti-arthritic agents, our laboratory has developed an ex vivo method for transferring genes encoding therapeutic proteins to the lining of the joint. This proposal is designed to evaluate the therapeutic efficacy of different inhibitors of TNF-alpha in blocking antigen induced arthritis when delivered to the joint by gene transfer. The specific aims are: 1) To construct retroviral vectors expressing monovalent and bivalent forms of TNF soluble receptors p55 and p75.2) To express the mono- and bivalent TNF-alpha soluble receptors intraarticularly in the rabbit knee by transplantation of genetically modified synoviocytes. 3) To determine the efficacy of each expressed TNF inhibitor in the treatment of antigen-induced arthritis in rabbit knee joints. 4) To determine the efficacy of coexpressing TNF-alpha inhibitors and interleukin-l receptor antagonist protein in the treatment of antigen-induced arthritis in rabbit knee joints. The results of these experiments should lead to identification of the appropriate therapeutic protein(s) to be used in further clinical trials for treatment of arthritis by gene transfer.